Male/Female Gene Expression Differs Brainwide

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Differences between the “male brain” and the “female brain” preoccupy pop psychologists and serious neuroscientists alike, but these differences seldom attract the scrutiny of molecular biologists. That may be changing, however, with the widening application of genome-wide analyses. As indicated by a recent study, such analyses are putting male/female brain differences in a molecular context.

The study, conducted by scientists based at the University College London, focused on gene expression, and it determined that sex differences in gene expression and splicing are widespread in adult human brain, occurring in all major brain regions and involving 2.5% of all expressed genes.

These results were presented November 22 in Nature Communications, in an article entitled “Widespread sex differences in gene expression and splicing in the adult human brain.” This article describes how investigators gained access to postmortem adult human brain and spinal cord samples originating from 137 neuropathologically confirmed control individuals. After taking samples from 12 different regions of the central nervous system for each individual, investigators subjected all of the samples to transcriptome profiling, generating the data needed for whole-genome analysis.

To explore the possibility of sex-biased gene regulatory architectures, the investigators conducted an expression quantitative trait loci (eQTL) analysis with the aim of finding significant interactions between sex and genotype. This analysis, the authors wrote, not only indicated that sex-biased gene expression in the adult human brain is widespread, it also suggested that, in some cases, “molecular differences are likely to have functional consequences relevant to human disease,” and, finally, that “sex biases in expression may reflect sex-biased gene regulatory structures.”

Of particular interest to the investigators was alternative splicing, a process in which a single gene may code for multiple proteins. Although alternative splicing is a normal process that greatly increases the diversity of proteins that can be encoded by the genome, it is also implicated in disease. For example, certain splicing variants are associated with brain disorders.

In one of the study's many subinquiries, the researchers looked at NRXN3, a gene that has been implicated in autism. NRXN3 is transcribed in two major isoforms, α-neurexins and β-neurexins. Although the study determined that α-neurexins are expressed similarly in both men and women, β-neurexins are produced at lower levels in women in the area of the brain called the thalamus. Such observations could help explain the higher incidence of autism in males.

The study’s senior author Mina Ryten, Ph.D., is clear about the value of genomics in clarifying the molecular basis of observed sex differences in structure, neurochemistry, behavior, and susceptibility to disease: “There is strong evidence to show that men and women differ in terms of their susceptibility to neurological diseases, but up until now the basis of that difference has been unclear.”

“Our study provides the most complete information so far on how the sexes differ in terms of how their genes are expressed in the brain,” Dr. Ryten adds. “We have released our data so that others can assess how any gene they are interested in is expressed differently between men and women.”